Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Abstract

Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases. Metabotropic glutamate (mGlu) receptors belong to a large family of G protein-coupled receptors largely expressed in neurons as well as in glial cells. They often appear overexpressed in areas involved in neurodegeneration, where they can modulate glutamatergic transmission. Of note, mGlu receptor upregulation may involve microglia or, even more frequently, astrocytes, where their activation causes release of factors potentially able to influence neuronal death. The expression of mGlu receptors has been also reported on oligodendrocytes, a glial cell type specifically involved in the development of multiple sclerosis. Here we will provide a general overview on the possible involvement of mGlu receptors expressed on glial cells in the pathogenesis of different neurodegenerative disorders and the potential use of subtype-selective mGlu receptor ligands as candidate drugs for the treatment of neurodegenerative disorders. Negative allosteric modulators (NAM) of mGlu5 receptors might represent a relevant pharmacological tool to develop new neuroprotective strategies in these diseases. Recent evidence suggests that targeting astrocytes and microglia with positive allosteric modulators (PAM) of mGlu3 receptor or oligodendrocytes with mGlu4 PAMS might represent novel pharmacological approaches for the treatment of neurodegenerative disorders.

Keywords: apoptosis; metabotropic glutamate receptor; neurodegeneration; neuroprotection; transforming growth factor-β1.

FIGURE 1

The role of mGlu receptors in different glial cell types. Astrocytes express both mGlu3 and mGlu5 receptors. mGlu3 receptor stimulation initiates mechanisms that induce neuroprotection, while mGlu5 receptor activity promotes neuronal damage. Hence, allowing pharmacological activation of mGlu 3 receptor (GO!) and blocking mGlu5 receptor activity (STOP) in astrocytes could be valuable for the maintenance of neuronal health. Similarly, in microglia, mGlu3 receptor stimulation plays beneficial effects on neurons (GO!), while blockade of mGlu2 (STOP) appears necessary to prevent neurotoxicity. Less defined is the function of glial mGlu5 receptor that, playing a dual role, may be a more complex target for pharmacological intervention (Alert yellow sign). Pharmacological activation of both mGlu1 and mGlu4 receptors, expressed in oligodendrocytes, appear to be neuroprotective (GO! sign).